This application focuses on understanding the pathophysiology following aneurysmal subarachnoid hemorrhage (aSAH). Many studies highlight the complications that aSAH survivors endure; however there is a dearth of research that address the underlying, potentially alterable pathophysiology, and disruption that lead to the occurrence and severity of post aSAH complications, severely hindering the development of appropriate interventions. DNA methylation is a key mechanism for regulation of gene expression and function in the adult brain and appears to play an important role in neuroprotection during ischemic events in the brain. Delayed cerebral ischemia (DCI), occurring during the acute phase following aSAH, is a major contributor to the complications that later develop; however the pathophysiology of DCI and the development of complications is not known. We hypothesize that characterizing the methylome representing the CNS environment post aSAH will clarify the pathophysiology associated with DCI and patient outcomes. The aims of this project focus on the daily genome-wide methylomic changes that occur in DNA representing the CNS for the first 14 days after aSAH using state of the science, high-throughput, genomic based methodologies; determining if this methylomic data impacts DCI as well as the development of complications after aSAH; using the genome-wide data to determine genes and pathways that experience methylomic changes over the 14 days after aSAH and have an impact DCI and complications; further investigate sites nominated by the genome-wide methylomic data using a ChIP-Seq approach; and through the use of an independent cohort of aSAH survivors the data will undergo a replication test as well as assessment for predictive value. This project brings together a truly multidisciplinary research team, which includes human geneticists, statistical geneticists, clinical experts in neurotrauma, and clinical experts in acut symptoms and chronic complications after aSAH. The ultimate goal and the overall impact of this project is to provide an understanding of the dynamic processes that occur after aSAH to obtain information that, in the future, will lead to the development of interventions that can be delivered after aSAH to reduce the occurrence of DCI, improve the CNS environment post aSAH, and ultimately reduce the burden of complications in the aSAH survivor. PUBLIC HEALTH RELEVANCE: Aneurysmal subarachnoid hemorrhage (aSAH) is a form of stroke that affects an estimated 30,000 individuals in the United States each year. Many studies highlight the complications that aSAH survivors endure; however very little research has addressed the underlying processes that lead to the occurrence and severity of post aSAH complications. This project will clarify these processes by exploiting new genomic technologies to better understand how methylation of the genome after aSAH impacts the occurrence of symptoms and complications in the aSAH survivor.